Non-winterized, standardized marine source oil products and methods of making thereof

ABSTRACT

Disclosed is a liquid medicament/supplement composition including a non-winterized marine source oil (e.g., oil derived from fish, krill, and/or squid), a food grade or pharmaceutically acceptable form of vitamin D 3  or a derivative thereof admixed in the non-winterized marine source oil, a food grade or pharmaceutically acceptable form of vitamin A or a derivative thereof admixed in the non-winterized marine source oil, optionally a food grade or pharmaceutically acceptable form of CoQ10 or a derivative thereof admixed in the non-winterized marine source oil, a food grade or pharmaceutically acceptable form of concentrated eicosapentaenoic acid and docosahexaenoic acid or ethyl ester, glyceride ester or salt of the acid and polyphenol rich vegetable oil admixed in the non-winterized marine source oil, and optionally a food grade or pharmaceutically acceptable form of melatonin or a derivative thereof admixed in the non-winterized marine source oil. The liquid medicament/supplement composition preferably has an oxidation amount measured as totox of less than 5, and the liquid medicament/supplement composition preferably has an overall eicosapentaenoic acid to docosahexaenoic acid ratio (EPA:DHA) ranging from 2:1 to 1:2 at a concentration ranging from 15 to 35 wt % of total liquid weight calculated as weight % of the corresponding free acid.

TECHNICAL FIELD

The present invention relates generally to the field of marine sourceoils including fish oil(s), and more particularly, to non-winterized,standardized marine source oil product(s) having a totox of 5 or lessand fixed EPA/DHA ratios.

BACKGROUND

Throughout history eating fish has been associated with good health,fertility, and helpful in alleviating many illnesses. In the late 1700sa clinic in Manchester, England discovered that cod liver oilmiraculously “healed” chronic pain from arthritis and the news spreadquickly across Europe and gave rise to the popularity of the oil.

In the 1970s, two Danish researchers theorized that the cardiac benefitsof eating fish were linked to a fatty acid group called the Omega 3s,which make up approximately 10 to 30 wt % of extracted fish oil whilethe remainder of the oil is comprised of saturated, mono unsaturated,and other poly unsaturated parts. Among the Omega 3 fatty acids, twofatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA))were particularly prevalent and garnered great scientific and popularnotoriety. However, researchers ignored the fact that, for example, codliver oil not only contains EPA and DHA but also more than 10 othertypes of Omega 3 fatty acids. Moreover, many fish oils includeendogenous vitamins such as Vitamins A, D, E, Cofactors such as CoQ10,and melatonin, but ratios and concentrations of these vitamins,cofactors, and melatonin vary dramatically across fish species.

Due to the positive effects associated with fish oils, many clinicaltrials have been conducted with various fish oils, DHA formulations, EPAformulations, and/or DHA/EPA formulations, but these trials generallyignore the fact that concentrations of fatty acids, vitamins, cofactors,and melatonin vary dramatically across fish species. Moreover, thesetrials further ignore how this variation affects a subject's epigeneticresponse (e.g., gene expression) when administered with theseformulations. The ultimate consequence is that clinical trials onlyquantify EPA/DHA efficacy while concurrently failing to quantifyefficacy of other active nutrients and freshness factor, which studiesare beginning to show are also important for fish oil potency.

To further complicate matters in Omega 3 research and clinical medicine,different Omega 3 molecules have different physiological actions, andfor the two main Omega 3 molecules (EPA and DHA), the science communityis divided on their use and/or importance. One group advocates using EPAalone since EPA may be stronger anti inflammation substance than DHAwhile other groups advocate that DHA is most important since it is thelongest molecule and the most likely to be lacking in one's diet. DHA isespecially known for its nerve cell building abilities and crucial formental functioning. It would therefore be advantageous to have an agreedupon EPA/DHA ratio that would be suitable to a multitude of medicalconditions.

Other problems often associated with fish oils are the off-putting odorand taste (e.g., a “fishy” smell and/or taste), which acts as adeterrent for supplementing ones diet with these oils/supplements. Theseoff-putting odors and tastes are attributed to oxidation of theunsaturated fatty acids as Omega-3 fatty acids and other chemicalcomponents in fish oils (“oxidized fish oils”) during fish storage andthe fish oil (i) rendering/purification, (ii) manufacture, and (iii)finished product storage processes. To make these oxidized fish oilsmore palatable, artificial flavoring(s) and taste masking agents areoften added to further improve taste and increase the likelihood ofconsumption of these oxidized fish oils. In some instances, theseoxidized fish oils are encapsulated within an encapsulating agent,including, for example, a thick gelatin coating/layer, which masks thefishy smells and tastes to increase ones desire to consume theseoxidized fish oils. However, even though encapsulating fish oils may aidin masking the fishy smell, it should be further noted that fish oiloxidation continues to occur post-encapsulation—often increasing by morethan 7.5 PoV and doubling in anisidine values (i.e., increased totox)within three weeks post-encapsulation. It should also be noted thatthese masking and encapsulating agents fail to completely obviate the“fishy” taste and smell, while also disadvantageously increasingproduction costs and manufacturing time for fish oil formulations.

Although masking agents and/or encapsulating agents are used as thecurrent industry-wide solution to overcome the fishy smell and taste ofthese oxidized fish oils, a major underlying problem remains.Specifically, oxidized fish oils have decreased health benefits,decreased bioavailability, and increased toxicity attributed to (i)increased totox (i.e., totox>10) and (ii) decreased EPA and DHAconcentrations (and ratios relative to each other) resulting fromprocessing (i.e., extraction and purification) when compared to totoxand EPA and DHA concentrations (and ratios relative to each other) innatural, endogenous fish oil in viable fish. It should be further notedthat fish oil oxidation cannot be reversed. Thus, once fish oil becomesoxidized and/or rancid it remains oxidized thereby permanently havingdecreased health benefits and decreased bioavailability. Also, theproducts formed during the oxidation of oils (rancemates) areunsaturated aldehydes and ketones as well as other reactive unsaturatedaliphatic hydrocarbons, known to be toxic.

In addition to the above mentioned problems, most, if not all, currentlyavailable fish oil(s)/fish oil supplements have been winterized (i.e.,fractionated) thereby excluding some beneficial fatty acids initiallypresent in these oils. Specifically, winterization is known in the artas the removal of glycerides (fat) with a melting point >0° C. from fishoil, thus potentially enhancing storability of these oils in lowtemperature environments. Winterization may occur by cooling the “neatfish oil” to approximately 0° C. thereby forming a liquid (oil)/crystalmixture and then separating the liquid portion (“olein”) from thesolid/crystalline portion (“stearin”). As the stearin portion containsmany valuable chemical components including various fatty acids that actsynergistically with the olein portion, winterized oils may havedecreased bioavailability and decreased health benefits due to theremoval of the stearin portion. In addition to decreased bioavailabilityof winterized fish oil, winterization of fish oils adds increasedcomplexity, increased cost, and increased time period(s) formanufacture/production of fish oil formulations.

Another major problem plaguing currently marketed fish oils (i.e., bothover the counter and prescription fish oil formulations) is the lack ofstandardization in these formulations. In other words, fish oilformulations vary greatly in, for example, fatty acid content (e.g.,Omega-3 fatty acid content, as well as Omega-6, 7, 9, 11, and 13 fattyacid content), EPA and DHA concentrations (and ratios relative to eachother), and totox thereby resulting in vastly different physiologicaland medical benefits obtained from these formulations. For example, manycurrently marketed formulations only include (i) concentrated EPA, (ii)concentrated DHA, and/or (iii) concentrated mixtures of EPA and DHA, butthese formulations lack (or are highly deficient) in other importantOmega-3 fatty acids such alpha-Linolenic acid (ALA), eicosadienoic acid(EDA), and docosapentaenoic acid (DPA), as well as Omega-6, 7, 9, 11 and13 fatty acids that are typically found in natural fish oils but areremoved when producing these concentrated EPA and/or DHA formulations.Unlike natural fish oils which have a neutral charge, these concentratedEPA formulations, concentrated DHA formulations, and/or concentratedmixtures of EPA and DHA have high in ethyl ester content resulting inincreased polarity and thereby lowering the viscosity of the oil whichmay affect its physiological functioning. As another example, (i)Omega-3 content and (ii) EPA and DHA concentrations and ratios greatlyvary in non-concentrated “natural” fish oils depending on the fish oilsource (i.e., the type of fish used to produce the oil), time of theyear the fish were obtained, the location from which the fish wereobtained, and the refinement methods used to render/purify the fish oil.These factors also result in highly variable physiological and medicalbenefits. Furthermore, reduced viscosities of concentrated and/orwinterized fish oils will also reduce its ability to be included infunction foods or topical formulations like skin cream as the oil willmore easily separate from solids and will also make addedmicro-encapsulated drugs included in fish oil medicinal formulationsmore noticeable and less palatable.

Another set of problems is connected to non-standardization of vitaminco factors in fish oil, e.g. Vitamin A and D₃. While the original andhighly potent cod liver oil contains significant amounts of Vitamin A(up to 1000 IU/g) and D₃ (up to 100 IU/g) most fish oils on the markettoday have low levels of these nutrients because they are lost duringthe purification process and refining of the oil. Since many researchersbelieve that Vitamin A and D₃ are important co factors for proper Omega3 function, some set/standardized values would be desirable.

Another important nutrient/hormone relevant to Omega 3 oil is thecontent of melatonin. This indole hormone is present in significantamounts in raw cod liver oil or tuna oil, but will typically bediminished during winterization and refining or in oil from fish in aquaculture where light is used to delay sex maturation (the light makesmelatonin content in fish diminish). Since studies show that melatoninand Omega 3 exercise synergistic actions on a multiple of cell metabolicfunctions, it would be desirable to restore and/or supplement thisamount but in many countries health authorities forbid adding melatoninto food.

As evidenced above, vast differences exist between the currentlymarketed fish oils, thus leading to vastly different physiological andmedical benefits observed by users of these formulations. Thus, for atleast the reasons, the above mentioned non-standardized fish oils,oxidized fish oils, winterized fish oils, and/or oxidized, winterizedfish oils present multi-faceted problem(s) of decreased bioavailability,decreased health benefits, and/or highly unpredictable health benefitscoupled with increased toxicity.

SUMMARY

Therefore, a need exists to provide compositions, along with methods ofmaking these compositions that obviate the above mentioned industry-wideproblems. Disclosed are standardized compositions formulated to minimizeand/or eliminate the vast physiological and medical differences observedin the currently marketed over the counter and prescription marinesource oil formulations (e.g., fish oil, krill oil, and/or squid oil)regardless of the original marine source. These standardizedcompositions can be used in clinical medicine and will not differ inessential content independent of whether the source is, for example, codliver, herring, krill, and/or squid. The present invention is alsoimportant for environmental reasons because there aren't enough rawmaterials to cover the world's need of fish oil from a single marinesource. Thus, the solution is to provide a standardized marine sourcedoil (standardized composition) that can use most marine sources as rawmaterials and still maintain the most valuable active ingredients in thesame concentrations and ratios that are found, for example, in fresh,non-modulated raw fish oil. It is preferred that these standardized oilscan be precisely reproduced batch after batch, stable over time, andhave qualities making it useful for Omega 3 supplementation, functionalfoods, skin cream applications or medical devices. As discussed infurther detail below, these standardized formulations preferably includea non-winterized marine source oil having a low totox that are producedutilizing a process as disclosed in, for example, WO2015/085045 “Omega-3Fatty Acid Articles Of Manufacture, And Methods And Apparatus ForMaking” to Martinsen et al., the disclosures of which are herebyincorporated by reference in their entirety. This non-winterized marinesource oil is further supplemented with desired amounts of EPAconcentrate, DHA concentrate, along with vegetable polyphenol rich oillike Flax seed oil or extra virgin olive oil (EVOO), lipophilicvitamins, and other desired chemical components (while maintaining lowtotox) to obtain a specified, standardized Omega-3 content and EPA/DHAconcentration(s) and ratio(s) regardless of the marine source therebyresulting in a composition having consistent, predictable healthbenefits. In certain aspects, it is preferable to supplement thenon-winterized marine source oil with EPA and/or DHA and polyphenol richvegetable oil by adding a small amount of EPA concentrate, DHAconcentrate, or mixtures thereof and small amounts of polyphenol richvegetable oil to adjust EPA and DHA concentrations and ratios to adesired amount without disturbing the natural fatty acid balance in thenon-winterized marine source oil. For example, in certain preferredaspects, if EPA and DHA concentration(s) are higher than desired atleast one of flax seed oil, extra virgin olive oil, and/or a polyphenolrich vegetable oil may be added to dilute the overall concentration ofEPA and/or DHA to obtain a standardized, desired EPA and/or DHAconcentration in the liquid medicament(s)/supplement(s). Thesecompositions are further preferably odorless, tasteless, or acombination thereof, thereby improving user/patient compliance byavoiding objections to the composition's taste.

Specifically disclosed are liquid medicament/supplement composition(s)including a non-winterized marine source oil, a pharmaceuticallyacceptable form of vitamin D₃ or derivative thereof admixed in thenon-winterized marine source oil, a pharmaceutically acceptable form ofvitamin A or a derivative thereof admixed in the non-winterized marinesource oil, a food grade or pharmaceutically acceptable form ofvegetable polyphenol rich oil admixed in the non-winterized marinesource oil, optionally a pharmaceutically acceptable form of CoenzymeQ10 (CoQ10) or a derivative thereof admixed in the non-winterized marinesource oil, concentrated eicosapentaenoic acid or, glyceride ester,ethyl ester or salt of the acid, concentrated docosahexaenoic acid, orglyceride ester, ethyl ester or salt of the acid or mixtures thereofadmixed in the non-winterized marine source oil, and optionally apharmaceutically acceptable form of melatonin or a derivative thereofadmixed in the non-winterized marine source oil. The liquidmedicament/supplement composition preferably has an oxidation amount(measured as totox) of 5 or less, and the liquid medicament/supplementcomposition preferably has an overall eicosapentaenoic acid todocosahexaenoic acid ratio (DHA:EPA) ranging from 2:1 to 1:2 in aconcentration ranging from 15 to 35 wt %. As alluded to above, incertain preferred aspects, if EPA and DHA concentration(s) are higherthan desired at least one of flax seed oil, extra virgin olive oil,and/or a polyphenol rich vegetable oil may be added to dilute theoverall concentration of EPA and/or DHA to obtain a standardized,desired EPA and/or DHA concentration in the liquidmedicament(s)/supplement(s). However, it is preferred to limit overallconcentration of flax seed oil, extra virgin olive oil, and/or apolyphenol rich vegetable oil to a concentration of less than 25 wt % oftotal liquid weight, less than 20 wt % of total liquid weight, less than15 wt % of total liquid weight, or less than 10 wt % of total liquidweight.

In certain aspects, the liquid medicament/supplement composition istasteless, odorless, or a combination thereof.

In certain aspects, melatonin is present in the liquidmedicament/supplement composition.

In certain aspects, the overall DHA:EPA ratio of the liquidmedicament/supplement composition more preferably ranges from 1.5:1 to1:1.5 and is most preferably 1:1. In certain aspects the overall DHA/EPAconcentration of the liquid medicament/supplement composition morepreferably ranges from 15 to 35 wt % of total liquid weight and is mostpreferably 25 wt % of total liquid weight.

In certain aspects, the liquid medicament/supplement composition isadapted for oral delivery, transdermal delivery, transmucosal delivery,or any combination thereof.

In certain aspects, the liquid medicament/supplement composition may beencapsulated in a capsule for gastro-intestinal delivery.

In certain aspects, the non-winterized marine source oil is at least onecomprising fish liver oil, cod liver oil, fish body oil, fish eye oil,fish meat oil, fish offal oil, oil from squid, oil from krill, or anycombination thereof. In certain aspects, the non-winterized marinesource oil is a fish oil including at least one of Norwegian Cod LiverOil, Alaskan Cod Liver Oil, Peruvian fish body oil, South African fishbody oil, Moroccan fish body oil, or any combination thereof. Examplesof cod liver oil include liver oil from any of the Gadidae family, andmay more specifically include liver oil from: Gadus morhua (Arctic cod,Atlantic cod), Gadus microcephalus (pacific cod), Pollachius vixens(seith, pollock, pollack), Pollachius pollochius (lyr), Melanogrammusaeglefinus (hyse, haddock), or any combination thereof. Additional liveroil from sharks (e.g., Elasmobranchii) may also be used as the source ofthe non-winterized marine source oil. Fish oil and/or oil fromadditional marine sources used in the non-winterized marine source oilmay further include oil from any one of the following: Scombridae (e.g.,Scombrus scombrus (mackerel), Thunnus (tunafish class), Engraulusringens, (anchoveta), Sardinella (e.g., Sardinella longicheps)(sardines), Clupea (Clupea harengus) (atlantic herring), Mallotus (e.g.,Mallotus villosus) (lodde), Salmonidae (e.g., Salmo salar, Salmo truttatrutta) (Atlantic salmon and trout), Todarodes sagittatus (akkar, squid,callimari), Calanidae (e.g., Calanus finmarchicus), Euphausiacea (e.g.,Meganyctiphanes norvegica) (krill), or any combination thereof.

Also disclosed are methods of producing the liquid medicament/supplementcomposition(s) including providing a non-winterized marine source oilhaving a totox of less than 5; admixing a pharmaceutically acceptableform of vitamin D₃ or a derivative thereof in the non-winterized marinesource oil; admixing a pharmaceutically acceptable form of vitamin A ora derivative thereof in the non-winterized marine source oil; optionallyadmixing a pharmaceutically acceptable form of CoenzymeQ10 or aderivative thereof salt thereof in the non-winterized marine source oil;adjusting eicosapentaenoic acid or ethyl ester, glyceride ester or saltof the acid concentration in the non-winterized marine source oil,docosahexaenoic acid or ethyl ester, glyceride ester or salt of the acidconcentration in the non-winterized marine source oil, or a combinationthereof by admixing concentrated eicosapentaenoic acid, or ethyl ester,glyceride ester or salt of the acid, concentrated docosahexaenoic acid,or ethyl ester, glyceride ester or salt of the acid a combinationthereof and polyphenol rich vegetable oil with the non-winterized marinesource oil (having a concentration of less than 25 wt % of total liquidweight); and optionally admixing melatonin or a salt thereof in thenon-winterized marine source oil thereby producing the liquidmedicament/supplement composition, wherein: the liquidmedicament/supplement composition has a totox of less than 5, and theliquid medicament/supplement composition has liquidmedicament/supplement composition has an overall eicosapentaenoic acidto docosahexaenoic acid ratio (DHA:EPA) ranging from 2:1 to 1:2 andhaving a concentration of 15 to 35 wt % of the medicament/supplement. Incertain aspects, the admixed concentrated eicosapentaenoic acid, orethyl ester, glyceride ester or salt of the acid, concentrateddocosahexaenoic acid, or ethyl ester, glyceride ester or salt of theacid a combination thereof is present at a concentration of less than 20wt %, less than 15 wt %, less than 10 wt %, less than 5 wt %, or lessthan 2 wt % of the total liquid weight.

In certain aspects, preferred containers are used for storing thedisclosed liquid medicament/supplement compositions that preferablylimit and/or eliminate the composition's oxidation while stored therein.For example this container may include an internal chamber containing aliquid medicament/supplement composition, and a cap that threadlyengages a top portion of the internal chamber to seal the internalchamber, the cap having an inverted nipple such that the internal nippleprotrudes into the internal chamber when the cap threadly engages thetop portion of the internal chamber thereby reducing and/or limiting airwithin the internal chamber thereby reducing and/or eliminatingoxidation of the liquid medicament/supplement while stored in thecontainer.

In certain aspects, the features of disclosed compositions (e.g., astandardized composition including a non-winterized marine source oilhaving a predetermined Omega-3 fatty acid content, a predetermined EPAand/or DHA content, and predetermined vitamin content) make thecompositions ideal for medical multipurpose use in combination withfoods, drugs, topical creams, and ointments because predictablephysiological and medical benefits may be consistently obtained withthese compositions.

Additional features, aspects and advantages of the invention will be setforth in the detailed description which follows, and in part will bereadily apparent to those skilled in the art from that description orrecognized by practicing the invention as described herein. It is to beunderstood that both the foregoing general description and the followingdetailed description present various embodiments of the invention, andare intended to provide an overview or framework for understanding thenature and character of the invention as it is claimed. The accompanyingdrawings are included to provide a further understanding of theinvention, and are incorporated in and constitute a part of thisspecification.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects and advantages of the presentinvention are better understood when the following detailed descriptionof the invention is read with reference to the accompanying drawings, inwhich:

FIGS. 1A and 1B depict a sealable container adapted to reduce oxidationof the non-winterized, standardized marine source oil product whilestored therein.

DETAILED DESCRIPTION

The present invention will now be described more fully hereinafter. Itis to be understood that the aspects described below are not limited tospecific compounds, synthetic methods, or uses as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular aspects only and is notintended to be limiting. However, the invention may be embodied in manydifferent forms and should not be construed as limited to therepresentative embodiments set forth herein. The exemplary embodimentsare provided so that this disclosure will be both thorough and complete,and will fully convey the scope of the invention and enable one ofordinary skill in the art to make, use and practice the invention.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not. For example, the phrase “optionally melatonin” means thatmelatonin may or may not be present in the compositions and/or methodsdescribed herein.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be“slightly above” or “slightly below” the endpoint without affecting thedesired result.

“Non-winterized” as disclosed herein refers to a non-concentrated marinesource oil containing both stearin and olein portions in whichglycerides having a melting point >0° C. have not been removed from themarine source oil via separation methods (e.g., fractionation,centrifugation, chromatographic techniques), as well as a full spectrumof Omega-3 fatty acids and Omega-6, 7, 9, 11, and 13 fatty acids foundin the marine oil source and being present in the marine source oil.

“Standardized” as disclosed herein refers to the supplementation of thenon-winterized marine source oil obtained after extracting the oil fromthe desired marine source (e.g., Norwegian cod, Alaskan cod, Peruvianfish body, South African fish body, Moroccan fish body, krill, squid)with, for example, DHA and/or EPA concentrate and Omega 3 fatty acids toobtain a desired concentration in the non-winterized, standardizedmarine source oil. Standardization further means that the contemplatedcomposition(s) can be precisely reproduced batch after batch over timeand with acceptable chemical stability under optimal storage conditions.

“Totox” is a well-established scientific notation for the oxidationlevel of an oil product containing unsaturated fatty acid moieties andreadily understood by those skilled in the art. A “low oxidation” as setforth by the Global Organization for EPA and DHA Omega 3s “GOED”(http://goedOmega3.com/) is a totox of less than 10. PoV is measured asmilliequivalents hydroperoxide(s) per kilogram of oil. PoV isincreasingly seen with millimoles per kg of oil as unit. This unit giveshalf the numeric value of the milliequivalent calculation. TOTOX wouldthen be 4xPoV+AiV. AiV is a number without units (it is the blue lightabsorption of compounds formed by reaction between an aldehyde (orketone) and anisidine. The procedure is an official American OilchemistsSociety “AOCS” procedure (method).

“Marine source oil(s)” as disclosed herein refers to oil(s) extractedfrom a desired marine source including fish, krill, and/or squid) usinga rendering and/or purification method that minimizes oxidation therebyresulting in totox <5. Preferably the marine source oil isrendered/purified through the method(s) disclosed in WO2015/085045“Omega-3 Fatty Acid Articles Of Manufacture, And Methods And ApparatusFor Making” to Martinsen et al. Exemplary marine sources forproviding/rendering the marine source oil(s) include: fish liver oilfrom any of the Gadidae family, and may more specifically include liveroil from: Gadus morhua (Arctic cod, Atlantic cod), Gadus microcephalus(pacific cod), Pollachius virens (seith, pollock, pollack), Pollachiuspollochius (lyr), Melanogrammus aeglefinus (hyse, haddock), or anycombination thereof. Additional liver oil from sharks (e.g.,Elasmobranchii) may also be used in the non-winterized marine sourceoil. Fish oil and/or oil from additional marine sources used in thenon-winterized marine source oil may further include oil from any one ofthe following: Scombridae (e.g., Scombrus scombrus (mackerel), Thunnus(tunafish class), Clupeidae (e.g.,Engraulus ringens)(anchoveta),Sardinella (e.g., Sardinella longicheps) (sardines), Clupea (Clupeaharengus) (atlantic herring), Mallotus (e.g., Mallotus villosus)(lodde), Salmonidae (e.g., Salmo salar, Salmo trutta trutta) (Atlanticsalmon and trout), Todarodes sagittatus (akkar, squid, callimari),Calanidae (e.g., Calanus finmarchicus), Euphausiacea (e.g.,Meganyctiphanes norvegica) (krill), or any combination thereof.

“Non-winterized standardized marine source oil” means a marine sourceoil as defined above that has not been subjected to winterization andthat has been (i) supplemented with a DHA and/or EPA concentrate andvegetable polyphenol rich oil to obtain desired DHA/EPA concentration(s)and ratio(s), (ii) supplemented with the vitamin(s), optional cofactors,optional melatonin, and optional additive(s) described herein, and (iii)further has a specifically desired Omega-3 fatty acid concentrationwhile having and/or maintaining a totox of less than 10 and mostpreferably 5 or less during production and storage (i.e., until consumedby a patient and/or user). The phrase “liquidmedicament(s)/supplement(s)” is used interchangeably with the phrase“non-winterized standardized marine source oil” throughout thisdisclosure.

“Food grade” means FDA approved use for human or animal nutrition.

“Pharmaceutical grade” means FDA approved for medicinal use.

“Admixed” means to mix with or mixed together such that components aredispersed in the composition. If the composition is liquid, thesecomponents are sufficiently mixed such that the components do notprecipitate out of solution, and in certain aspects, these componentsare homogeneously mixed/admixed and/or dispersed in the liquidmedicament(s)/supplement(s).

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within theranges as if each numerical value and sub-range is explicitly recited.As an illustration, a numerical range of “about 1 to 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc. as well as 1, 2, 3, 4, and 5, individually. The sameprinciple applies to ranges reciting only one numerical value as aminimum or a maximum. Furthermore, such an interpretation should applyregardless of the breadth of the range or the characteristics beingdescribed.

The compositions and methods described herein can comprise, consist of,or consist essentially of the essential elements and limitationsdescribed herein, as well as any additional or optional ingredients,components, or limitations described herein or otherwise useful innutritional formula applications.

It is understood that any given particular aspect of the disclosedcompositions and methods can be easily compared to the specific examplesand embodiments disclosed herein. By performing such a comparison, therelative efficacy of each particular embodiment can be easilydetermined. Particularly preferred compositions and methods aredisclosed in the Examples herein, and it is understood that thesecompositions and methods, while not necessarily limiting, can beperformed with any of the compositions and methods disclosed herein.

In certain aspects, disclosed are liquid medicament/supplementcomposition(s) that include a non-winterized marine source oil, a foodgrade or pharmaceutically acceptable form of vitamin D₃ or a derivativethereof admixed in the non-winterized marine source oil, a food grade orpharmaceutically acceptable form of vitamin A or a derivative thereofadmixed in the non-winterized marine source oil, a food grade orpharmaceutically acceptable form of CoQ10 or a derivative thereofadmixed in the non-winterized marine source oil, a food grade orpharmaceutically acceptable form of concentrated eicosapentaenoic acidand/or docosahexaenoic acid admixed in the non-winterized marine sourceoil, a food grade or pharmaceutically acceptable form of vegetablepolyphenol rich oil admixed in the non-winterized marine source oil, andoptionally a food grade or pharmaceutically acceptable form of melatoninor a derivative thereof admixed in the non-winterized marine source oil.The liquid medicament/supplement composition preferably has an oxidationamount (measured as totox) of 5 or less, and the liquidmedicament/supplement composition preferably has an overalleicosapentaenoic acid to docosahexaenoic acid ratio (DHA:EPA) rangingfrom 2:1 to 1:2 in a concentration ranging from 15 to 35 wt % of totalliquid weight. The liquid medicament/supplement composition(s) ispreferably odorless and tasteless—not having a fishy taste or smell. Incertain preferred aspects, this liquid medicament/supplement compositionmost preferably has a DHA:EPA ratio of 1:1 at a concentration of 25 wt %of total liquid weight. The below disclosures provide further detailregarding the individual components of the liquidmedicament(s)/supplement(s).

Non-Winterized Marine Source Oil

As discussed above, the liquid medicaments/supplements disclosed hereininclude non-winterized marine source oil derived preferably from, forexample, fish, krill, and/or squid. Examples may include Norwegian Cod,Norwegian Cod Liver, Alaskan Cod, Alaskan Cod Liver, Peruvian fish body,South African fish body, Moroccan fish body, or any combination thereof.Exemplary fish liver oils may be from any fish in the Gadidae family,and may more specifically include liver oil from: Gadus morhua (Arcticcod, Atlantic cod), Gadus microcephalus (pacific cod), Pollachius virens(seith, pollock, pollack), Pollachius pollochius (lyr), Melanogrammusaeglefinus (hyse, haddock), or any combination thereof. Additional liveroil from sharks (e.g., Elasmobranchii) may also be used in thenon-winterized marine source oil. Fish oil and/or oil from additionalmarine sources used in the non-winterized marine source oil may furtherinclude oil from any one of the following: Scombridae (e.g., Scombrusscombrus (mackerel), Thunnus (tunafish class), Clupeidae (e.g.,Engraulus ringens)(anchoveta), Sardinella (e.g., Sardinella longicheps)(sardines), Clupea (Clupea harengus) (atlantic herring), Mallotus (e.g.,Mallotus villosus) (lodde), Salmonidae (e.g., Salmo salar, Salmo truttatrutta) (Atlantic salmon and trout), Todarodes sagittatus (akkar, squid,callimari), Calanidae (e.g., Calanus finmarchicus), Euphausiacea (e.g.,Meganyctiphanes norvegica) (krill), or any combination thereof. Anon-winterized marine source oil is preferred because this oil includesa complete fatty acid profile of both the above mentioned olein andstearin portions as well as Omega-6, 7, 9, 11, and 13 fatty acids thatsynergistically act to provide optimal health benefits including, butnot limited to, reducing endogenous, cellular inflammation, reducing therisk of heart disease, increasing fertility, having positive effects onfetal development in utero, regulating fat metabolism, and aiding visualacuity. The non-winterized marine source oil may be preferably obtainedby using extraction/purification processes as disclosed in WO2015/085045“Omega-3 Fatty Acid Articles Of Manufacture, And Methods And ApparatusFor Making” to Martinsen et al., the disclosures of which are herebyincorporated by reference in their entirety. During these processes,antioxidants and melatonin are preferably added to limit oxidation(e.g., maintaining a totox of less than 10 and preferably 5 or less)while rendering/purifying the non-winterized marine source oil.

By limiting non-winterized marine source oil oxidation duringprocessing, improved physiological effects may be achieved whileconcurrently avoiding marine source oil rancidity and toxicity. Forexample, in certain preferred aspects, the non-winterized oil maintainsa totox of less than 10, more preferably less than 7.5, and mostpreferably 5 or less throughout extraction/purification and in theliquid medicament(s)/supplement(s). In certain aspects, thenon-winterized marine source oil maintains a totox range from 2.5 to 10,from 2.5 to 7.5, from 3 to 8, from 3 to 6, from 4 to 8, from 4 to 6,from 4 to 5.5 throughout (i) extraction/purification and (ii) in thedisclosed liquid medicament(s)/supplement(s).

To further obtain desired bioavailability and beneficial health effects,it is desired that the non-winterized marine source oil have specifiedconcentrations/amounts of Omega-3 fatty acids to obtain a desired,standardized Omega-3 fatty acid concentration in the liquidmedicament(s)/supplement(s). In the non-winterized marine source oil,overall Omega-3 fatty acid concentration is from 15 to 35 wt/wt %, from22 to 35 wt/wt %, from 24 to 30 wt/wt %, or from 24 to 28 wt/wt %. Incertain aspects, the overall Omega-3 fatty acid concentration in theliquid medicament(s)/supplement(s) ranges from 20 to 30 wt/wt %, from 22to 38 wt/wt %, or from 24 to 26 wt/wt %. In certain preferred aspects,overall Omega-3 fatty acid concentration in the liquidmedicament(s)/supplement(s) is about 24 wt/wt %, about 25 wt/wt %, about26 wt/wt %, or about 27 wt/wt %.

DHA and EPA Concentration(s) and Ratio(s)

To further enhance bioavailability and beneficial health effects of theliquid medicament(s)/supplement(s), it is also preferable to supplementthe non-winterized marine source oil with food grade and/orpharmaceutical grade EPA and/or DHA by adding a small amount of EPAconcentrate, DHA concentrate, or mixtures thereof to adjust EPA and DHAratios to a desired amount without disturbing the natural fatty acidbalance in the non-winterized marine source oil, thereby obtaining adesired, standardized EPA/DHA ratio(s) and then to admix polyphenol richvegetable oil like flax seed oil to obtain the desired EPA/DHA oilconcentration in the final liquid medicament/supplement regardless ofthe source of the marine oil. The standardization of EPA/DHAconcentration(s) and ratio(s) further ensures that consistentphysiological and medical benefits are achieved when using the liquidmedicament(s)/supplement(s) regardless of the source of the marine oil.When supplementing the non-winterized marine source oil with the DHAand/or EPA concentrate(s) and vegetable oil, it is further required tomaintain a totox of less than 10, more preferably less than 7.5, andmost preferably 5 or less. In certain aspects, the non-winterized marinesource oil maintains a totox range from 2.5 to 10, from 2.5 to 7.5, from3 to 8, from 3 to 6, from 4 to 8, from 4 to 6, from 4 to 5.5 duringsupplementation with the DHA and/or EPA concentrate(s) and polyphenolrich vegetable oil.

In certain aspects, it is desired that the liquidmedicament(s)/supplement(s)have an overall DHA:EPA ratio ranging from2:1 to 1:2, more preferably 1.5:1 to 1:1.5, even more preferably 1.25:1to 1:1.25, and most preferably 1:1, wherein DHA and/or EPAconcentrations in the non-winterized marine source oil were adjusted tohave these ratios by adding small amounts of EPA and/or DHA concentratesto the non-winterized marine source oil. In certain aspects, overall DHAconcentration in the liquid medicament(s)/supplement(s) ranges from 8 to20 wt %, 10 to 17 wt %, or 12 to 16 wt %. In certain aspects, overallEPA concentration in the liquid medicament(s)/supplement(s) ranges from8 to 20 wt %, 10 to 17 wt %, or 12 to 16 wt %. When present in themedicament(s)/supplement(s), concentrated eicosapentaenoic acid or ethylester, glyceride ester or salt of the acid, concentrated docosahexaenoicacid or ethyl ester, glyceride ester or salt of the acid, or mixturesthereof admixed in the non-winterized marine source oil are present at aconcentration of less than 20 wt % of total liquid weight, at aconcentration of less than 15 wt % of total liquid weight, at aconcentration of less than 10 wt % of total liquid weight, at aconcentration of less than 5 wt % of total liquid weight, or at aconcentration of less than 2 wt % of total liquid weight. In certainaspects, DHA and EPA are present in the medicament(s)/supplement(s) atan overall concentration ranging from 15 to 35 wt % of total liquidweight, from 20 to 30 wt % of total liquid weight, or from 22 to 27 wt %of total liquid weight. In certain aspects, it is desired that theliquid medicament(s)/supplement(s)have an overall DHA:EPA ratio rangingfrom 2:1 to 1:2, more preferably 1.5:1 to 1:1.5, even more preferably1.25:1 to 1:1.25, and most preferably 1:1 at an overall concentrationranging from 15 to 35 wt % of total liquid weight, from 20 to 30 wt % oftotal liquid weight, or from 22 to 27 wt % of total liquid weight. Incertain preferred aspects, the overall DHA:EPA ratio is 1:1 having anoverall DHA and EPA concentration of 25 wt % of total liquid weight.

Vitamin(s)

To further enhance bioavailability and beneficial health effects of theliquid medicament(s)/supplement(s), lipophilic vitamins are additionallyadmixed with the non-winterized marine source oil along with the DHA/EPAconcentrate. Examples of lipophilic vitamins include a food grade orpharmaceutically acceptable form of Vitamin A (retinol/beta carotene) ora derivative thereof, a food grade or pharmaceutically acceptable formof Vitamin D (e.g., Vitamin D₂ and/or D₃) or a derivative thereof, afood grade or pharmaceutically acceptable form of Vitamin E (tocopherolsor trinutriols) or a derivative thereof, and a food grade orpharmaceutically acceptable form of Vitamin K₁ and/or K₂ or a derivativethereof. In certain aspects, Vitamin C in, for example, oil soluble formmay also be included in the liquid medicament(s)/supplement(s). Inaddition to the enhanced bioavailability of the liquidmedicament(s)/supplement(s), the lipophilic vitamin(s) concurrently andadvantageously act to sequester oxygen radicals (e.g., free radicals),thereby reducing and/or preventing oxidation in these liquidmedicament(s)/supplements. Specifically, when admixing the vitamin(s),it is preferred that this mixture maintains a totox of less than 10,more preferably less than 7.5, and most preferably 5 or less.

The liquid medicament(s)/supplement(s) may specifically include a foodgrade or pharmaceutically acceptable form of Vitamin A or a derivativethereof, a food grade or pharmaceutically acceptable form of Vitamin D(e.g., Vitamin D₂ and/or D₃) or a derivative thereof, a food grade orpharmaceutically acceptable form of Vitamin E or a derivative thereof, afood grade or pharmaceutically acceptable form of Vitamin K or aderivative thereof, or any combination thereof. Each of these lipophilicvitamins may be independently present in the liquidmedicament/supplement at concentrations ranging from, for example, 20 to500 IU/ml oil and/or from 15 to 500 mg/g oil. In certain aspects, atleast a food grade or pharmaceutically acceptable form of Vitamin A or aderivative thereof and a food grade or pharmaceutically acceptable formof Vitamin D₃ or a derivative thereof are included in the liquidmedicament(s)/supplement(s) because of physiologically synergisticeffects with the non-winterized oil and their antioxidant abilities Theconcentration of Vitamin A or the derivative thereof in the liquidmedicament(s)/supplement(s) ranges from 50 to 200 IU/ml oil, from 75 to150 IU/ml oil, from 100 to 125 IU/ml oil. The concentration of VitaminD₃ or the derivative thereof in the liquid medicament(s)/supplement(s)ranges from 25 to 200 IU/ml oil, from 50 to 175 IU/ml oil, 75 to 150IU/ml oil, or from 100 to 125 IU/ml oil. The concentration of Vitamin Eor the derivative thereof in the liquid medicament(s)/supplement(s)ranges from 15 to 100 mg/g oil, from 25 to 90 mg/g oil, from 45 to 75mg/g oil, or from 60 to 70 mg/g oil.

Cofactors

To also further enhance bioavailability and beneficial health effects ofthe liquid medicament(s)/supplement(s), one or more cofactors may beoptionally admixed in the non-winterized marine source oil along withthe above mentioned DHA and/or EPA concentrate, vegetable polyphenolrich oil and vitamins while maintaining a totox of less than 10, morepreferably less than 7.5, and most preferably 5 or less. In certainaspects, these cofactors are non-vitamin cofactors including, but notlimited to, a food grade or pharmaceutically acceptable form of CoenzymeQ (Coenzyme Q10) or a derivative thereof, a food grade orpharmaceutically acceptable form of Coenzyme B or a derivative thereof,a food grade or pharmaceutically acceptable form of Coenzyme M or aderivative thereof, adenosine triphosphate (ATP or a salt thereof), orany combination thereof.

The above mentioned non-vitamin cofactors may each be independentlypresent in the liquid medicament(s)/supplement(s) at a concentrationranging from 0.3 to 10 mg/ml oil. Of particular interest and importanceamong these cofactors is the food grade or pharmaceutically acceptableform of Coenzyme Q10 or a derivative thereof. Without wishing to bebound by theory, Coenzyme Q10 is thought to work in synergy with Omega 3fatty acids and melatonin in the cellular/mitochondria energy chaises.Thus, in certain preferred aspects, Coenzyme Q10 or a derivative thereofis admixed/supplemented into the non-winterized marine source oil alongwith the above mentioned DHA and/or EPA concentrate(s), vegetable oiland vitamins at a concentration ranging from 0.3 to 10 mg/ml oil, from 1to 7 mg/ml oil, from 2 to 5 mg/ml oil to further supplement Coenzyme Q10concentrations naturally occurring in the marine source oil therebypotentially ensuring optimal bioavailability and beneficial healtheffects of the liquid medicament(s)/supplement(s).

Melatonin

A food grade or pharmaceutically acceptable form of melatonin orderivative thereof may also be optionally admixed to the non-winterizedmarine source oil having the above mentioned non-winterized marinesource oil, the DHA and/or EPA concentrate, vitamin(s), and cofactor(s)while maintaining a totox of less than 10, more preferably less than7.5, and most preferably 5 or less when preparing the liquidmedicament(s)/supplement(s). Melatonin is an important hormone thatregulates circadian rhythm in animals, thus helping maintain a propersleep/wake cycle in addition to being a very effective anti-oxidant/freeradical scavenger. Melatonin has also been implicated blood pressureregulation, immunomodulation (e.g., regulating inflammation), andreducing symptoms associated with many autoimmune disorders. It shouldbe further noted that few scientifically proven adverse side effectshave ever been documented from melatonin supplementation. The chemicalstructure of melatonin is shown below as Formula I.

Moreover, melatonin has antioxidant properties, which are desirable inorder to maintain low totox (i.e., of less than 10, more preferably lessthan 7.5, and most preferably 5 or less) of the liquidmedicament(s)/supplement(s). An important characteristic of melatoninthat distinguishes it from other classic radical scavengers/antioxidantsis that its metabolites are also scavengers in what is referred to as acascade reaction. Thus, even if melatonin is degraded/breaks down, itsmetabolites may still function as antioxidants to sequester freeradicals, thus preventing oxidation of, for example, the liquidmedicament(s)/supplement(s) disclosed herein. Without wishing to bebound by theory, melatonin is also thought to synergistically interactwith other antioxidants, for example, lipophilic vitamins such asVitamin A, Vitamin D (e.g., Vitamin D₃), and/or Vitamin E to enhanceoverall antioxidant properties and effectiveness. Melatonin has beenproven to be twice as active as vitamin E, which is believed to be themost effective lipophilic vitamin antioxidant. Also different from manyother antioxidants, such as vitamin E, melatonin has amphiphilicproperties, which may further allow this compound to interact with bothlipophilic and hydrophilic portions of cells and/or tissues in animals.Thus, melatonin clearly displays the above mentioned positive benefitsand may be included in the disclosed liquid medicament(s)/supplement(s)for at least these reasons. Depending on the desired affect (e.g.,antioxidant, antiinflammation/anti-inflammatory, etc.) in themedicament(s)/supplement(s), melatonin may be added to the disclosedliquid medicament(s)/supplement(s) at various concentrations. Whenincluded in the disclosed liquid medicament(s)/supplement(s), melatoninor the salt thereof is present at a concentration of up to 100 mg, up to75 mg, up to 50 mg, up to 25 mg, up to 10 mg, up to 5 mg, or up to 3 mg.For example, when included in the disclosed liquidmedicament(s)/supplement(s), melatonin or the salt thereof is present ata concentration of from 0.1 mg to 100 mg, from 0.1 mg to 75 mg, from 0.1mg to 50 mg, from 0.1 mg to 25 mg, from 0.1 mg to 10 mg, from 0.1 mg to5 mg, from 3 mg to 100 mg, from 3 mg to 75 mg, from 3 mg to 50 mg, from3 mg to 25 mg, from 3 mg to 10 mg, from 10 mg to 100 mg, from 10 mg to75 mg, from 10 mg to 50 mg, from 10 mg to 25 mg, from 25 mg to 100 mg,from 25 mg to 75 mg, from 25 mg to 50 mg, from 25 mg to 35 mg, from 40mg to 100 mg, from 40 mg to 75 mg, from 40 mg to 50 mg, from 65 mg to100 mg, from 65 mg to 85 mg, from 65 mg to 75 mg, from 65 mg to 70 mg,from 80 mg to 100 mg, from 80 mg to 95 mg, from 80 mg to 90 mg, from 80mg to 85 mg, from 85 mg to 100 mg, from 85 mg to 95 mg, from 85 mg to 90mg, from 90 mg to 100 mg, from 90 mg to 95 mg, or from 95 mg to 100 mg.In lower concentrations of melatonin are desired, melatonin may bepresent in the liquid medicament(s)/supplement(s) at a concentrationranging from 0.1 mg to 3 mg, from 0.15 mg to 2.5 mg, from 0.15 to 2.0mg, from 0.175 mg to 2.0 mg, from 0.175 mg to 1.75 mg, from 0.175 mg to1.5 mg, from 0.2 mg to 1.5 mg, from 0.2 mg to 1.75 mg, from 0.2 mg to1.5 mg, from 0.2 mg to 1.25 mg, or from 0.2 mg to 1.0 mg.

Optional Additives

In addition to the above mentioned components, the liquidmedicament(s)/supplements disclosed herein may further include optionaladditives. For example and although the disclosed liquidmedicament(s)/supplement(s) are essentially odorless and tasteless dueto low totox, natural or artificial flavorings may be added to theliquid medicament(s)/supplement(s) to provide a desired taste to thesemedicament(s)/supplement(s). Natural or artificial flavorings mayinclude fruit punch, orange, lemon, or any known flavorings atsufficient concentration(s) to provide the medicament/supplement withthe desired taste. One skilled in the art would readily understand howto admix these flavorings to the medicament(s)/supplement(s) to providethe desired taste. Likewise, one skilled in the art would readilyunderstand how to provide natural or artificial fragrance(s) to thesemedicament(s)/supplement(s) if an odor/smell is desired.

Other additives may include, for example, lutein, astaxanthin,resveratrol, fatty alcohols (waxes), beta glucan, lecithin,phospholipids (e.g., phosphatidylcholine, phosphatidylserine,phosphatidylinositol), green tea or extracts thereof, or any combinationthereof.

Delivery Forms

Any combination of food grade and pharmaceutical grade compositions ofany of the above non-winterized marine source oil(s), DHA and/or EPAconcentrate(s), polyphenol rich vegetable oil, vitamin(s) or saltsthereof, cofactors or salts thereof, melatonin or salts thereof, andoptional additives may be used when formulating the liquidmedicament(s)/supplement(s), and these liquidmedicament(s)/supplement(s) can be formulated in any excipient thebiological system or entity can tolerate. Nonaqueous vehicles, such asfixed oils, vegetable oils such as olive oil, flax seed oil and sesameoil, propylene glycol, and polyethylene glycol can also be used tofurther enhance delivery and efficacy of the liquidmedicament(s)/supplement(s). Other useful formulations includesuspensions containing viscosity enhancing agents, such as sodiumcarboxymethylcellulose, sorbitol, dextran, xanthan, lecithin, betaglucan, hyaluronic acid, glycerin. Excipients can also contain minoramounts of additives, such as substances that enhance isotonicity andchemical stability. Examples of buffers include phosphate buffer,bicarbonate buffer and Tris buffer, while examples of preservativesinclude thimerosol, cresols, formalin and benzyl alcohol andphenoxyethanol.

Food grade and pharmaceutical grade carriers are known to those skilledin the art. These most typically would be standard carriers foradministration to humans and animals, including solutions such asbuffered solutions at physiological pH.

Food grade and pharmaceutical grade compositions can include carriers,thickeners, diluents, buffers, preservatives, surface active agents andthe like in addition to the molecule of choice.

The disclosed liquid medicament(s)/supplement(s) compositions can beadministered in a number of ways depending on whether local or systemictreatment is desired, and on the area to be treated. Administration canbe orally, sublingually, transdermally, and/or transmucosally.

Formulations for administration can include ointments, lotions, creams,gels, drops, sprays, liquids and capsules. Because the liquidmedicaments/supplements disclosed herein have higher viscosity thanother currently marketed fish, krill, and/or squid oils, the disclosedliquid medicaments/supplements can be used by itself as food supplement,in cosmetic or topical creams or ointments, suppositories, vaginalapplications, eye drops, mouth wash, and will be more stable asingredient in functional foods like fortified cookies, chocolates, saladdressings, fruit juices and smoothies with lower risk of water/oilseparation.

Dosing is dependent on severity and responsiveness of the condition tobe treated, but will normally be one or more doses per day, with courseof treatment lasting from several days to several months or until one ofordinary skill in the art determines the delivery should cease. Personsof ordinary skill can easily determine optimum dosages, dosingmethodologies and repetition rates. For example, the disclosed liquidmedicament(s)/supplement(s) may be provided sublingually to preventand/or treat, for example, periodontitis (i.e., preventing and/orreducing buccal inflammation especially related to the gum lineinflammation). The medicament(s)/supplement(s) disclosed herein may beuseful in eye lotions or drops to prevent and/or treat dry eye syndrome,cataracts, burns, bed sores, chronic wounds, eczema, psoriasis,vaginitis, various dermatoses, post-surgery scarring (e.g., keloidscarring), skin cancers, sun burn and skin damage associated with sunburns, and/or may be used as a prophylactic skin treatment due to itsanti-aging skin effects. It is understood that any given particularaspect of the disclosed compositions and methods can be easily comparedto the specific examples and embodiments disclosed herein based reagentsdiscussed in the Examples. By performing such a comparison, the relativeefficacy of each particular embodiment can be easily determined.Particularly preferred compositions and methods are disclosed in theExamples herein, and it is understood that these compositions andmethods, while not necessarily limiting, can be performed with any ofthe compositions and methods disclosed herein.

Packaging of Liquid Medicament/Supplement Composition(s)

In certain embodiments, the liquid medicament(s)/supplement(s) may bepackaged and/or stored in specialized containers that further limitoxidation. As shown in FIGS. 1A and 1B, a container 100 including aninternal chamber 110 containing the disclosed liquidmedicament/supplement composition(s) 150 is disclosed. Container 100further includes cap 120 having an inner diameter portion 121 adapted tothreadly engage a top, outer diameter portion 111 of internal chamber110 to seal the internal chamber along with the contents stored/housedtherein (i.e., the disclosed liquid medicament(s)/supplement(s)). Cap120 has an inverted nipple 122 that protrudes into the internal chamberwhen the cap threadly engages the top portion of the internal chamberthereby forcing air (i.e., oxygen and other gases) out of the internalchamber, which further limits/reduces oxidation of the disclosedmedicament(s)/supplement(s) stored therein.

In certain aspects, the internal chamber 110 is formed of glass (and/oran oxygen barrier film) and cap 120 is formed of a thermoplastic resin(and/or an oxygen barrier film), each being having minimal electrondonors and receptors on its surface thereby further limiting theoccurrence of redox reactions between the container 100 and liquidmedicament(s)/supplement(s) 150 stored/housed therein. This beneficiallyminimizes oxidation of the liquid medicament(s)/supplement(s) until auser opens cap 120 to use the liquid medicament(s)/supplement(s). Ifglass is used as the internal chamber, this glass may further be surfacetreated to further minimize the occurrence of redox reactions betweenthe container 100 and liquid medicament(s)/supplement(s) 150.

In certain aspects, a single dose of the disclosed liquidmedicament/supplement composition is included in the container 100.Container 100 volume capacity can vary, but in certain aspects,container 100 can store 1 mL to 20 mL, 1 mL to 10 mL 5 mL to 20 mL, 5 mLto 15 mL, or 5 mL to 10 mL of the disclosed liquidmedicament/supplement, which may be used for clinical trials and/or forgeneral product presentation to the end user.

WORKING EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, and methods described and claimed herein aremade and evaluated, and are intended to be purely exemplary and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers (e.g., amounts, temperature, etc.) but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C. or is at ambienttemperature, and pressure is at or near atmospheric.

I. Comparison Between Exemplary Non-Winterized Standardized MarineSource Oil (Liquid Medicament/Supplement) and Other Currently MarketedExemplary Fish and Krill Oils

Table 1 below depicts a comparison between the chemical components andoxidation amounts between an exemplary non-winterized standardizedmarine source oil (liquid medicament/supplement) and other exemplaryfish and krill oils currently on the market. In Table 1, “Concentrate”refers to Omega 3 wt % concentration>30. Examples of “Concentrate”include Dr. Sear's, concentrated Omega 3 from Nordic Naturals. In Table1, “Prescription” refers to a standard prescription formulation havingan Omega 3 wt % concentration >85% Exemplary “Prescription” fish oilincludes Omacore/Lovaza® and Epanova®. In Table 1, “18/12” refers toblended fish oil from herring, sardine, mackerel having a 30 wt %EPA/DHA concentration. In Table 1, “Salmon” refers to fish oil fromsalmon having a 8 to 16 wt % EPA/DHA concentration. In Table 1, “Krill”refers to oil from krill, typically around 16% concentration in itsnatural form but varies from 7 to 24 wt % depending on the commercialformulation. In Table 1, “Non-Winterized, Standardized Marine SourceOil” refers to the “Non-Winterized, Standardized Marine Source Oil” ofthe present invention.

TABLE 1 Omega-3 Non- DHA:EPA Oxydation Vitamin Vitamin (wt/wt %)Winterized Ratio (totox) D3 (IU) A CoQ10 Concentrate >30 — Variable >5 —— — for (10-20) different brands Prescription >85 — Variable >5 — — —for (10) different brands 18/12  30 — 2/1 >5 — — — (10-30) Salmon 8-16 —1/1 >5 — — — (10-20) Krill 7-24 — 2/1 >5 — — — (10-50) Non-  25 + 1/1 <5800/ 25%/ 5 mg/ Winterized, 15 ml 15 ml 15 ml Standardized Marine SourceOil

As shown in Table 1, “Non-Winterized, Standardized Marine Source Oil”(sourced from Norwegian cod liver) is a non-winterized oil that exhibitsconsiderably less totox, a predetermined 1/1 DHA:EPA ratio, along withpredetermined Omega-3, Vitamin D₃, and Vitamin A concentrations whencompared with currently available over the counter and prescriptionformulations.

II. Odor and Taste Test Comparison Between Exemplary Non-WinterizedStandardized Marine Source Oil and Other Currently Marketed ExemplaryFish Oils

Table 2 below depicts an exemplary taste and smell test between fish andkrill oils currently on the market and the exemplary non-winterized,standardized marine source oil having the formulation disclosed inTable 1. As evidenced by Table 2, the “concentrate” fish oil,“prescription” fish oil, “18/12” fish oil, salmon oil, and krill oil,exhibited a noticeable, undesirable fishy odor when each sample wassmelled and an undesirable, “fishy/fish taste” during the taste test.However, the exemplary non-winterized, standardized marine source oildid not exhibit taste or odor.

TABLE 2 Tasteless* Odorless* Concentrate No No Prescription No No 18/12No No salmon No No Krill No No Non-Winterized, Yes Yes StandardizedMarine Source Oil *Indicates Without Taste/Odor Masking Agents

The foregoing description provides embodiments of the invention by wayof example only. It is envisioned that other embodiments may performsimilar functions and/or achieve similar results. Any and all suchequivalent embodiments and examples are within the scope of the presentinvention and are intended to be covered by the appended claims.

What is claimed is:
 1. A liquid medicament/supplement compositioncomprising: (a) a non-winterized marine source oil from at least one offish, krill, squid, or any combination thereof; (b) a pharmaceuticallyacceptable form of vitamin D₃ or a derivative thereof admixed in thenon-winterized marine source oil; (c) a pharmaceutically acceptable formof vitamin A or a derivative thereof admixed in the non-winterizedmarine source oil; (d) optionally a pharmaceutically acceptable form ofCoenzyme Q10 or a derivative thereof admixed in the non-winterizedmarine source oil; (e) a polyphenol rich vegetable oil at aconcentration of less than 25 wt % of total liquid weight of thecomposition, (f) a concentrated eicosapentaenoic acid, an ethyl esterthereof, a glyceride ester thereof, or a salt thereof; a concentrateddocosahexaenoic acid, an ethyl ester thereof, a glyceride ester thereof,or a salt thereof; or mixtures thereof admixed in the non-winterizedmarine source oil at a concentration of less than 20 wt % of totalliquid weight of the composition; and (g) a pharmaceutically acceptableform of melatonin or a derivative thereof admixed in the non-winterizedmarine source oil, wherein: the liquid medicament/supplement compositionhas a totox of less than 5, and the liquid medicament/supplementcomposition has an overall eicosapentaenoic acid to docosahexaenoic acidratio (EPA:DHA) calculated as weight % free acids ranging from 2:1 to1:2 at a concentration ranging from 15 to 35 wt % of total liquid weightof the composition.
 2. The liquid medicament/supplement composition ofclaim 1, wherein the liquid medicinal composition is tasteless,odorless, or a combination thereof.
 3. The liquid medicament/supplementcomposition of claim 1, wherein melatonin or the derivative thereof ispresent in the liquid medicinal composition at a concentration of to 100mg.
 4. The liquid medicament/supplement composition of any of claim 1,wherein the overall EPA:DHA ratio in the liquid medicinal composition is1:1.
 5. The liquid medicament/supplement composition of claim 1, whereinthe liquid medicament/supplement composition is adapted for oraldelivery.
 6. The liquid medicament/ supplement composition of claim 1,wherein the liquid/ supplement composition is adapted for skin delivery,rectal delivery, vaginal delivery, or any combination thereof.
 7. Theliquid medicament/supplement composition of claim 1, wherein the liquidmedicament/supplement composition is encapsulated in a capsule forgastro-intestinal delivery.
 8. The liquid medicament/supplementcomposition of claim 1, wherein the non-winterized marine source oilcomprises at least cod oil and/or cod liver oil.
 9. The liquidmedicament/supplement composition of claim 1, wherein the non-winterizedmarine source oil is Norwegian Cod Liver Oil.
 10. A liquidmedicament/supplement composition consisting of: (a) a non-winterizedmarine source oil from at least one of fish, krill, squid, or anycombination thereof; (b) a pharmaceutically acceptable form of vitaminD₃ or a derivative thereof admixed in the non-winterized marine sourceoil; (c) a pharmaceutically acceptable form of vitamin A or a derivativethereof admixed in the non-winterized marine source oil; (d) optionallya pharmaceutically acceptable form of Coenzyme Q10 or a derivativethereof admixed in the non-winterized marine source oil; (e) apolyphenol rich vegetable oil at a concentration of less than 25 wt % oftotal liquid weight of the composition; (f) a concentratedeicosapentaenoic acid, an ethyl ester thereof, a glyceride esterthereof, or a salt thereof; a concentrated docosahexaenoic acid, anethyl ester thereof, a glyceride ester thereof, or a salt thereof; ormixtures thereof at a concentration of less than 20 wt % of total liquidweight of the composition; and (g) a pharmaceutically acceptable form ofmelatonin or a derivative thereof admixed in the non-winterized marinesource oil, wherein: the liquid medicament/supplement composition havinga totox of less than 5, and the liquid medicament/supplement compositionhas an overall eicosapentaenoic acid to docosahexaenoic acid ratio(EPA:DHA) calculated as weight % of the free acids ranging from 2:1 to1:2 at concentration ranging from 15 to 35 wt % of total liquid weightof the composition.
 11. A container comprising: a chamber containing aliquid medicament/ supplement composition, and a cap removably, threadlyengaged to a top portion of the chamber to seal the chamber, the caphaving an inverted nipple such that the internal nipple protrudes intothe chamber when the cap threadly engages the top portion of the chamberthereby reducing and/or limiting air within the chamber, wherein: theliquid medicament/supplement composition contained in the chamberconsists of: (a) a non-winterized marine source oil from at least one offish, krill, squid, or any combination thereof, (b) a pharmaceuticallyacceptable form of vitamin D₃ or a derivative thereof admixed in thenon-winterized marine source oil, (c) a pharmaceutically acceptable formof vitamin A or a derivative thereof admixed in the non-winterizedmarine source oil, (d) optionally a pharmaceutically acceptable form ofCoenzyme Q10 or a derivative thereof admixed in the non-winterizedmarine source oil, (e) a polyphenol rich vegetable oil at aconcentration of less than 25 wt % of total liquid weight of thecomposition; (f) a concentrated eicosapentaenoic acid, an ethyl esterthereof, a glyceride ester thereof, or a salt thereof; a concentrateddocosahexaenoic acid, an ethyl ester thereof, a glyceride ester thereof,or a salt thereof; or mixtures thereof, and (g) a pharmaceuticallyacceptable form of melatonin or a derivative thereof admixed in thenon-winterized marine source oil, wherein: the liquidmedicament/supplement composition having a totox of less than 5, and theliquid medicament/supplement composition has an overall eicosapentaenoicacid to docosahexaenoic acid ratio (EPA:DHA) ranging from 2:1 to 1:2 ina concentration ranging from 15 to 35 wt % of total liquid weightcalculated as weight % of the corresponding free acids.
 12. A method ofproducing a liquid medicament/supplement composition comprising:providing a non-winterized marine source oil; admixing apharmaceutically acceptable form of vitamin D₃ or a derivative thereofin the non-winterized marine source oil; admixing a pharmaceuticallyacceptable form of vitamin A or a derivative thereof in thenon-winterized marine source oil; optionally admixing a pharmaceuticallyacceptable form of Coenzyme Q10 or a derivative thereof salt thereof inthe non-winterized marine source oil; admixing a polyphenol richvegetable oil at a concentration of less than 25 wt % of total liquidweight of the composition in the non-winterized marine source oil;admixing melatonin or a salt thereof in the non-winterized marine sourceoil; and admixing a concentrated eicosapentaenoic acid, an ethyl estertherof, a glyceride ester therof, or a salt thereof; a concentrateddocosahexaenoic acid, an ethyl ester thereof, a glyceride ester thereof,or a salt thereof, or mixtures thereof in the non-winterized marinesource oil at a concentration of less than 20 wt % of total liquidweight of the composition in order to obtain the liquidmedicament/supplement composition; wherein the obtained liquidmedicament/supplement composition has a totox of less than 5, and anoverall eicosapentaenoic acid to docosahexaenoic acid ratio (EPA:DHA)calculated as weight % free acids ranging from 2:1 to 1:2 at aconcentration ranging from 15 to 35 wt % total liquid weight ofcomposition.
 13. The method of claim 12, wherein the concetration ofmelatonin in the liquid medicament/supplement is up to 100 mg.